The Atlas D missile was the natural choice for Project Mercury since it was the only launch vehicle in the US arsenal that could put the spacecraft into orbit. But its reliability was far from perfect and Atlas launches ending in explosions were an all-too common sight at Cape Canaveral. Thus, significant steps had to be taken to man-rate the missile and make it safe and reliable.

Central to these efforts was the development of the Abort Sensing and Implementation System, which would detect malfunctions in the Atlas's various components and trigger a launch abort if necessary. An overview of failed Atlas test flights had shown that in most cases, the missile displayed ample warning signs prior to total failure occurring. As such, it was fairly easy to set up the ASIS system to check for trouble. Added redundancy was built in; if ASIS itself failed, the loss of power would also trigger an abort. The system was tested on a few Atlas ICBM flights prior to Mercury-Atlas 1 in July 1960, where it was operated open-loop (MA-3 in April 1961 would be the first closed-loop flight).

The rate gyro package was placed much closer to the forward section of the LOX tank due to the Mercury/LES combination being considerably longer than a warhead and thus producing different aerodynamic characteristics (the standard Atlas D gyro package was still retained on the vehicle for the use of the ASIS)

The range safety system was also modified for the Mercury program. There would be a three-second delay between engine cutoff and activation of the destruct charges so as to give the LES time to pull the capsule to safety. To prevent an errant launch vehicle from coming down on or around the launch pad, the engines could not be cut off until at least 30 seconds into the flight.

The old-fashioned electromechanical autopilot on the Atlas was replaced by a solid-state model that was more compact and easier to service.

The guidance antenna was modified to reduce signal interference.

Combustion instability was an important problem that needed to be fixed. Although it normally only occurred in static firing tests of the MA-3 engine, there had been back-to-back Atlas pad explosions (Missiles 51D and 48D) caused by that situation. In lieu of this, it was decided to install extra sensors in the engines to monitor combustion levels and the booster would also be held down on the pad for a few moments after ignition to ensure smooth thrust. The engines would also use a "wet start" (meaning that the propellants were injected into the combustion chamber prior to igniter activation) which would eliminate rough ignition. If the booster failed the check, it would be automatically shut down. Once again, these upgrades required testing on Atlas R&D flights. By late 1961, Convair had developed a significantly upgraded propulsion system that featured baffled fuel injectors and a hypergolic igniter in place of the pyrotechnic method, but NASA was unwilling to jeopardize John Glenn's upcoming flight with these untested modifications and so declined to have them installed in Mercury-Atlas 6's booster. As such, that and Scott Carpenter's flight on MA-7 used the old-style Atlas propulsion system and the new variant was not employed until Wally Schirra's flight late in 1962.

The Atlas LOX turbopumps were equipped with plastic lining to prevent the scenario of the impellers rubbing against the casing and generating friction heat which would ignite the oxidizer and trigger an explosion (again, a problem mostly only seen in static tests, but it had occurred on Atlas 9C in September 1959 and would later befall Atlas 11F in April 1962).

After MA-1 was destroyed in-flight due to a structural failure, NASA began requesting that Convair deliver Atlases with thicker skin. Atlas 10D, the vehicle used for the Big Joe test in September 1959, had sported thick skin and verified that this was needed for the heavy Mercury capsule. Atlas 100D would be the first thick-skinned booster delivered while in the meantime, MA-2's booster (67D) which was still a thin-skinned model, had to be equipped with a steel reinforcement band at the interface between the capsule and the booster.

The vernier solo phase, which would be used on ICBMs to fine-tune the missile velocity after sustainer cutoff, was eliminated from the guidance program since it served no purpose on a space launch. Since orbital flights required an extremely different flight path from missiles, the guidance antennas had to be completely redesigned to ensure maximum signal strength. The posigrade rocket motors on the top of the Atlas, designed to push the spent missile away from the warhead, were moved to the Mercury capsule itself. This also necessitated adding a fiberglass insulation shield to the LOX tank dome so it wouldn't be ruptured by the rocket motors.

A common and normally harmless phenomenon on Atlas vehicles was the tendency of the booster to develop a slight roll in the first few seconds following liftoff due to the autopilot not kicking in yet. On a few flights however, the booster developed enough rolling motion to potentially trigger an abort condition if it had been a manned launch. Although some roll was naturally imparted by the Atlas's turbine exhaust, this could not account for the entire problem which instead had more to do with engine alignment. Acceptance data from the engine supplier (Rocketdyne) showed that a group of 81 engines had an average roll movement in the same direction of approximately the same magnitude as that experienced in flight. Although the acceptance test-stand and flight-experience data on individual engines did not correlate, it was determined that offsetting the alignment of the booster engines could counteract this roll motion and minimize the roll tendency at liftoff. After Schirra's Mercury flight did experience momentary roll problems early in the launch, the change was incorporated into Gordon Cooper's booster on MA-9.

It first flew on 29 July 1960, conducting the suborbital Mercury-Atlas 1 test flight. The rocket suffered a structural failure shortly after launch, and as a result failed to place the spacecraft onto its intended trajectory.[citation needed] In addition to the maiden flight, the first orbital launch, Mercury-Atlas 3 also failed. This failure was due to a problem with the guidance system failing to execute pitch and roll commands, necessitating that the Range Safety Officer destroy the vehicle. The spacecraft separated by means of its launch escape system and was recovered 1.8 kilometres (1.1 mi) from the launch pad.

A further series of Mercury launches was planned, which would have used additional LV-3Bs; however these flights were canceled after the success of the initial Mercury missions.[citation needed] The last LV-3B launch was conducted on 15 May 1963, for the launch of Mercury-Atlas 9.